Antigen receptor signaling in the rheumatic diseases

Julie Zikherman,Arthur Weiss

doi:10.1186/ar2528

Abstract

Antigen receptor signaling in lymphocytes has been clearly implicated in the pathogenesis of the rheumatic diseases. Here, we review evidence from mouse models in which B-cell and T-cell signaling machinery is perturbed as well as data from functional studies of primary human lymphocytes and recent advances in human genetics. B-cell receptor hyper-responsiveness is identified as a nearly universal characteristic of systemic lupus erythema-tosus in mice and humans. Impaired and enhanced T-cell receptor signaling are both associated with distinct inflammatory diseases in mice. Mechanisms by which these pathways contribute to disease in mouse models and patients are under active investigation.

Highlights

The classic concept of autoimmune disease rests upon the notion that the adaptive immune system generates inappropriate antigen-specific responses to self epitopes which in turn drive disease
Since the canonical definition of the adaptive immune response relates to the ability of somatic recombination to produce an enormous range of antigen receptors on lymphocytes, it follows that antigen receptor signal transduction ought to play a role in autoimmune diseases
Lyn is reciprocally regulated by CD45 and Csk and in turn phosphorylates B-cell antigen receptor (BCR) immunoreceptor tyrosine-based activating motifs (ITAMs) as well as immune tyrosine inhibitory motif (ITIM)-containing immunoreceptors

Summary

Introduction

The classic concept of autoimmune disease rests upon the notion that the adaptive immune system generates inappropriate antigen-specific responses to self epitopes which in turn drive disease. Lyn is reciprocally regulated by CD45 and Csk and in turn phosphorylates B-cell antigen receptor (BCR) immunoreceptor tyrosine-based activating motifs (ITAMs) as well as immune tyrosine inhibitory motif (ITIM)-containing immunoreceptors. B-cell antigen receptor signaling mutants and murine lupus Several single-gene mutants develop a lupus-like disease characterized by the production of anti-nuclear antibodies (ANAs) in the context of hyper-responsive BCR signaling.

Results

Conclusion